Abstract

Diagnostic identification of human genetic disorders causing male or female infertility is of paramount interest in each infertility
clinic dealing with the term ‘idiopathic infertility’, which means ‘no reason found for observed infertility pathology’. In
such cases, if there is a genetic disorder behind (in about 30%), there is usually a high risk of transfer of this genetic
lesion to the offspring by the applied fertilisation protocol. Such genetic‐based infertility disorders can be unbalanced
chromosome aberrations including aneuploidies and/or specific gene mutations, respectively. As comparative genomic hybridisation
(CGH) and next‐generation sequencing (NGS) tools have now shown that the normal human genome can have a highly variable sequence
composition, thus also in men and women with normal fertility, it has become a major challenge for the clinicians to then
identify only those genome/gene mutations which may indeed cause the observed infertility pathology.

Key Concepts

Genetic disorders can cause about 30% male and female infertility.

Analysis of chromosome aberrations (aneuploidies) is mandatory before ART application in ‘idiopathic’ male and female infertility.

Figure 1. Multiple genetic loci for the maintenance and progression of human folliculogenesis are located on the X chromosome. According
to the OMIM database they are summarised under POF1 (OMIM: #311360) with FMR1 as the most prominent POF candidate gene (because most frequently mutated), POF2 (OMIM: #300511 and #300604) and POF4 (OMIM:
#300247). Associated POF candidate genes, that is genes known to be expressed during human folliculogenesis, of which some
were already found with mutations in women with POI/POF syndrome, are listed at the right. For further description see the
text.

Figure 2. Schematic view of the CFTR exon structure with polymorphic (T)n tract at the intron 8 acceptor splice site (n = 5–9). In men with CBAVD, there is an increased frequency of the 5T variant causing most often (<90%) skipping of CFTR exon 9, which results in translation of the nonfunctional CFTR protein.

Figure 3. Schematic view of AZF gene content on the long arm of the human Y chromosome in Yq11. The pink coloured blocks mark the X–Y
homologous sequence blocks. It includes also the AZFa deletion interval. Homologous blocks in the ampliconic repetitive sequence
structure in distal Yq11 encompassing AZFb and AZFc deletion intervals are marked by the same colour code as designated by
Kuroda‐Kawaguchi et al. . The 19 protein encoding Y genes mapped in Yq11 and expressed in the male germ line are distinguished by specific colours
and represented by arrows with the corresponding 5′–3′ polarity (modified from Vogt et al., ).